EP3263572A1 - Procédé de production de kakéromycine et de ses dérivés - Google Patents

Procédé de production de kakéromycine et de ses dérivés Download PDF

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Publication number
EP3263572A1
EP3263572A1 EP16755707.3A EP16755707A EP3263572A1 EP 3263572 A1 EP3263572 A1 EP 3263572A1 EP 16755707 A EP16755707 A EP 16755707A EP 3263572 A1 EP3263572 A1 EP 3263572A1
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optionally substituted
group
formula
salt
compound represented
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EP3263572B1 (fr
EP3263572A4 (fr
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Teruhiko Ishikawa
Morita Iwami
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Op Bio Factory Co Ltd
Seed Research Institute Co Ltd
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Op Bio Factory Co Ltd
Seed Research Institute Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B33/00—Oxidation in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a production method of kakeromycin and a derivative thereof.
  • Marine microorganism resources have drawing attention. Marine microorganism resources have been scarcely utilized, and have a high possibility of affording a novel secondary metabolite.
  • Kakeromycin a new compound represented by the following formula: which was found from a microorganism collected from the seabed sand around the Kakeroma island of Kagoshima Prefecture, Amami Islands, was named "Kakeromycin”.
  • the "kakeromycin” shows an antifungal activity, particularly, a strong antibacterial activity against pathogens of candidiasis, highly possibly shows a new antibacterial action different from those of existing antifungal agents, and further research and development in the future is expected.
  • the "kakeromycin” shows cytotoxicity to HepG2 liver cancer cell and PANC-1 pancreas cancer cell, its development as an anticancer agent is expected.
  • An object of the present invention is to provide a method of producing kakeromycin and a derivative thereof by chemical synthesis.
  • the present inventors have conducted intensive studies in an attempt to solve the above-mentioned problem and found a method of producing kakeromycin and a derivative thereof represented by the following formula (1) by chemical synthesis, which resulted in the completion of the present invention.
  • the present invention provides the following.
  • kakeromycin and a derivative thereof which show an antifungal activity and cytotoxicity, and are expected as new antifungal agents and anticancer agents can be produced by chemical synthesis.
  • R, R 1 and R 2 are each an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • R 3 is an optionally substituted hydrocarbon group or an optionally substituted acyl group.
  • R 4 is an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon-oxy group.
  • hydrocarbon group of the “optionally substituted hydrocarbon group” and the “hydrocarbon-” (hydrocarbon moiety) of the “optionally substituted hydrocarbon-oxy group” include C 1-20 alkyl group, C 2-20 alkenyl group, C 2-20 alkynyl group, C 3-20 cycloalkyl group, C 3-20 cycloalkenyl group, C 6-20 aryl group, and C 7-20 aralkyl group.
  • C 1-20 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • C 2-20 alkenyl group examples include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.
  • C 2-20 alkynyl group examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.
  • C 3-20 cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.
  • C 3-20 cycloalkenyl group examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • C 6-20 aryl group examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • C 7-20 aralkyl group examples include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • heterocyclic group of the “optionally substituted heterocyclic group” examples include (i) aromatic heterocyclic group, (ii) nonaromatic heterocyclic group and (iii) 7- to 10-membered crosslinked heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom.
  • aromatic heterocyclic group examples include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered condensed polycyclic (preferably di- or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisooxazolyl, benzothiazoly
  • nonaromatic heterocyclic group examples include a 3- to 14-membered (preferably 4- to 10-membered) nonaromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom.
  • nonaromatic heterocyclic group examples include 3- to 8-membered monocyclic nonaromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl,
  • Preferable examples of the "7- to 10-membered crosslinked heterocyclic group” include quinuclidinyl, and 7-azabicyclo[2.2.1]heptanyl.
  • acyl group of the "optionally substituted acyl group” examples include formyl group, carboxy group, C 1-6 alkyl-carbonyl group, C 2-6 alkenyl-carbonyl group, C 3-10 cycloalkyl-carbonyl group, C 3-10 cycloalkenyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, aromatic heterocyclyl-carbonyl group, non-aromatic heterocyclyl-carbonyl group, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group, C 7-16 aralkyloxy-carbonyl group, and carbamoyl group.
  • C 1-6 alkyl-carbonyl group examples include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.
  • C 2-6 alkenyl-carbonyl group examples include ethenylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2-methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3-pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1-hexenylcarbonyl, 3-hexenylcarbonyl, and 5-hexenylcarbonyl.
  • C 3-20 cycloalkyl-carbonyl group examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo[2.2.1]heptylcarbonyl, bicyclo[2.2.2]octylcarbonyl, bicyclo[3.2.1]octylcarbonyl, and adamantylcarbonyl.
  • C 3-20 cycloalkenyl-carbonyl group examples include cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl, cycloheptenylcarbonyl, and cyclooctenylcarbonyl.
  • C 6-14 aryl-carbonyl group examples include benzoyl, 1-naphthoyl, and 2-naphthoyl.
  • C 7-16 aralkyl-carbonyl group examples include phenylacetyl, and phenylpropionyl.
  • aromatic heterocyclyl-carbonyl group examples include nicotinoyl, isonicotinoyl, thenoyl, and furoyl.
  • non-aromatic heterocyclyl-carbonyl group examples include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • C 1-6 alkoxy-carbonyl group examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.
  • C 6-14 aryloxy-carbonyl group examples include phenyloxycarbonyl, 1-naphthyloxycarbonyl, and 2-naphthyloxycarbonyl.
  • C 7-16 aralkyloxy-carbonyl group examples include benzyloxycarbonyl, and phenethyloxycarbonyl.
  • the number of the above-mentioned “substituent” of the "optionally substituted hydrocarbon group”, “optionally substituted hydrocarbon-oxy group”, “ optionally substituted heterocyclic group” and “ optionally substituted acyl group” is, for example, 1 to 5, preferably 1 to 3.
  • the respective substituents may be the same or different.
  • R is preferably an optionally substituted C 2-20 alkenyl group (e.g., ethenyl), more preferably, a group represented by the formula (A): wherein R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, more preferably, a group represented by the formula (A) wherein R 1 and R 2 are the same or different and each is an optionally substituted C 1-20 alkyl group (e.g., methyl) or an optionally substituted C 7-20 aralkyl group (e.g., benzyl), particularly preferably, a group represented by the formula (A) wherein R 1 and R 2 are the same or different and each is a C 1-20 alkyl group (e.g., methyl) or a C 7-20 aralkyl group (e.g., benzyl).
  • R 1 and R 2 are the same or different and each is a C 1-20 alkyl group (e.g.
  • R is preferably an optionally substituted C 2-20 alkenyl group (e.g., ethenyl), an optionally substituted C 1-20 alkyl group (e.g., heptyl), an optionally substituted C 6-20 aryl group (e.g., phenyl, naphthyl) or an optionally substituted C 7-20 aralkyl group (e.g., phenylethyl), more preferably, a group represented by the formula (A): wherein R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, an optionally substituted C 1-20 alkyl group (e.g., heptyl), an optionally substituted C 6-20 aryl group (e.g., phenyl, naphthyl) or an optionally substituted C 7-20 aralkyl group (e.g., phenylethyl), more preferably,
  • R 3 is preferably an optionally substituted C 1-20 alkyl group (e.g., methyl) or an optionally substituted C 1-6 alkyl-carbonyl group (e.g., acetyl), more preferably, a C 1-20 alkyl group (e.g., methyl) or a C 1-6 alkyl-carbonyl group (e.g., acetyl), further preferably, methyl or acetyl.
  • C 1-20 alkyl group e.g., methyl
  • C 1-6 alkyl-carbonyl group e.g., acetyl
  • R 4 is preferably an optionally substituted C 1-20 alkyl group (e.g., methyl), an optionally substituted C 6-20 aryl group (e.g., phenyl), an optionally substituted C 1-20 alkyl-oxy group (e.g., tert-butyloxy) or an optionally substituted C 7-20 aralkyl-oxy group (e.g., benzyloxy), more preferably a C 1-20 alkyl group (e.g., methyl), a C 6-20 aryl group (e.g., phenyl), a C 1-20 alkyl-oxy group (e.g., tert-butyloxy) or a C 7-20 aralkyl-oxy group (e.g., benzyloxy), further preferably, methyl, phenyl, tert-butyloxy or benzyloxy, particularly preferably tert-butyloxy.
  • C 1-20 alkyl group e.g.,
  • n is 0 or 1. n is preferably 1.
  • Oxime (8) can be synthesized by a dehydration condensation reaction of aldehyde (9) and hydroxylamine prepared from hydroxylamine hydrochloride and a base.
  • a base sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, tertiary amines such as triethylamine and the like, and the like can be used at generally 1 - 5 molar equivalents, preferably 1 - 1.5 molar equivalents, relative to hydroxylamine hydrochloride, and sodium hydrogen carbonate is particularly preferable.
  • Hydroxylamine hydrochloride can be used at generally 1 - 5 molar equivalents, preferably 1 - 1.5 molar equivalents, relative to aldehyde (9).
  • the reaction temperature is generally 0 - 50°C, preferably 20 - 30°C. While the reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 48 hr, preferably 2 - 10 hr.
  • As the reaction solvent THF, water, acetonitrile, ethyl acetate, dichloromethane, or a mixed solvent thereof and the like can be used, and a mixed solvent of THF-water is particularly preferable.
  • Aldehyde (9) may be a commercially available product, and can also be produced according to a method known per se or a method analogous thereto.
  • Dihydroisoxazole (6A, 6B) can be synthesized by (3+2) cyclization addition reaction of nitrile oxide prepared from oxime (8) and aqueous sodium hypochlorite solution, or oxime (8) and chloramine-T, and N-acylaminobutene (7A) or N-acylaminopropene (7B).
  • the aqueous sodium hypochlorite solution, or chloramine-T can be used at generally 1 - 5 molar equivalents, preferably 1 - 2 molar equivalents, relative to oxime 8.
  • Oxime (8) can be used at generally 0.5 - 3 molar equivalents, preferably 0.8 - 1.2 molar equivalents, relative to N-acylaminobutene (7A) or N-acylaminopropene (7B).
  • the reaction temperature is generally 0 - 80°C, preferably 20 - 30°C. While the reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 48 hr, preferably 2 - 10 hr.
  • As the reaction solvent THF, ethyl acetate, dichloromethane, ethanol, methanol, acetonitrile or a mixed solvent thereof and the like can be used.
  • N-acylaminobutene (7A) or N-acylaminopropene (7B) may be a commercially available product, and can also be produced according to a method known per se or a method analogous thereto.
  • N-acylaminohydroxyketone (5A, 5B) can be synthesized by reducing N-O bond of dihydroisoxazole (6A, 6B).
  • the reducing agent molybdenum hexacarbonyl, cobalt octacarbonyl, iron, zinc, magnesium and the like can be used at generally 1 - 5 molar equivalents, preferably 1 - 2 molar equivalents, relative to dihydroisoxazole (6A, 6B), though subject to change depending on the kind of the reagents, reaction temperature and the like, and molybdenum hexacarbonyl is particularly preferable.
  • the reaction temperature is generally 0 - 100°C, preferably 70 - 90°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 24 hr, preferably 1 - 3 hr.
  • reaction solvent acetonitrile, propionitrile, water, THF, ethyl acetate, dichloromethane, dichloroethane, or a mixed solvent thereof and the like can be used, and a mixed solvent of acetonitrile-water is particularly preferable.
  • Aminohydroxyketone (4A, 4B) can be synthesized by removing an acyl protecting group of the amino group of N-acylaminohydroxyketone (5A, 5B).
  • the deprotecting agent trifluoroacetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and the like can be used at generally 1 - 50 molar equivalents, preferably 1 - 10 molar equivalents, relative to N-acylaminohydroxyketone (5A, 5B), and trifluoroacetic acid is particularly preferable.
  • the reaction temperature is generally 0 - 50°C, preferably 20 - 30°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 24 hr, preferably 1 - 3 hr.
  • reaction solvent THF, ethyl acetate, dichloromethane, dichloroethane, or a mixed solvent thereof and the like can be used, and particularly, dichloromethane and dichloroethane are preferable.
  • Step 5 Production of cyclic hemiaminal 3A, 3B
  • Cyclic hemiaminal (3A, 3B) can be synthesized by an intramolecular addition reaction of aminohydroxyketone (4A, 4B). While an intramolecular addition reaction sometimes proceeds without particularly using a reaction agent, when an acid catalyst is necessary, trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, can be used at generally 0.01 - 5 molar equivalents, preferably 0.01 - 1 equimolar amount, relative to aminohydroxyketone (4A, 4B).
  • the reaction temperature is generally 0 - 100°C, preferably 30 - 50°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 24 hr, preferably 1 - 6 hr.
  • reaction solvent THF, ethyl acetate, dichloromethane, dichloroethane, toluene, or a mixed solvent thereof and the like can be used, and THF or dichloroethane is particularly preferable.
  • Cyclic imine (2A, 2B) can be synthesized by an intramolecular dehydration condensation reaction of cyclic hemiaminal (3A, 3B).
  • the dehydrating agent trifluoroacetic acid, acetic acid, molecular sieve, anhydrous sodium sulfate and the like can be used at generally 0.01 - 100 molar equivalents, preferably 0.01 - 10 molar equivalents, relative to cyclic hemiaminal (3A, 3B), though subject to change depending on the kind of the reagents, reaction temperature and the like.
  • the reaction temperature is generally 0 - 100°C, preferably 20 - 60°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 1 - 24 hr, preferably 3 - 12 hr.
  • reaction solvent THF, ethyl acetate, dichloromethane, dichloroethane, toluene, or a mixed solvent thereof and the like can be used, and THF is particularly preferable.
  • Bicyclic oxaziridine (1A, 1B) can be synthesized by an oxidation reaction of cyclic imine (2A, 2B).
  • cyclic imine (2A, 2B) As the oxidant, m-chloroperbenzoic acid, peracetic acid and the like can be used at generally 1 - 5 molar equivalents, preferably 1 - 2 molar equivalents, relative to cyclic imine (2A, 2B), and m-chloroperbenzoic acid is particularly preferable.
  • the reaction temperature is generally 0 - 50°C, preferably 10 - 30°C. While the reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 0.5 - 12 hr, preferably 1 - 2 hr.
  • reaction solvent THF, ethyl acetate, dichloromethane, dichloroethane, toluene, ethanol, methanol, acetonitrile, or a mixed solvent thereof and the like can be used, and THF and dichloromethane are particularly preferable.
  • Step 8 Production of bicyclic oxaziridine derivative 1-1A, 1-1B
  • the bicyclic oxaziridine derivative (1-1A, 1-1B) can be synthesized by protecting the hydroxyl group of bicyclic oxaziridine (1A, 1B).
  • the protection reaction can be performed using the corresponding halide as a protector and a base each at generally 1 - 10 molar equivalents, preferably 1 - 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B).
  • a halide methyl iodide is particularly preferable.
  • the base sodium carbonate, potassium carbonate, sodium hydride, n-butyllithium and the like can be used, and sodium hydride is particularly preferable.
  • the reaction temperature is generally 0 - 50°C, preferably 20 - 30°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 0.5 - 24 hr, preferably 1 - 12 hr.
  • reaction solvent THF, dimethyl sulfoxide, dimethylformamide, acetonitrile, dichloromethane, dichloroethane, or a mixed solvent thereof and the like can be used, and dimethyl sulfoxide or acetonitrile is particularly preferable.
  • the protection reaction can be performed using the corresponding halogenated acyl compound or acid anhydride as a protector at generally 1 - 10 molar equivalents, preferably 1 - 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B) in the presence of an amine base.
  • halogenated acyl compound or acid anhydride acetic anhydride is particularly preferable.
  • a tertiary amine such as triethylamine, diisopropylethylamine and the like, or a pyridine derivative such as pyridine, dimethylaminopyridine and the like can be used at generally 1 - 10 molar equivalents, preferably 1 - 3 molar equivalents, relative to the bicyclic oxaziridine derivative (1-1A, 1-1B), and triethylamine or dimethylaminopyridine is particularly preferable.
  • the reaction temperature is generally 0 - 50°C, preferably 20 - 30°C.
  • reaction time varies depending on the kind of the reagents, reaction temperature and the like, it is generally 0.5 - 24 hr, preferably 1 - 12 hr.
  • reaction solvent THF, ethyl acetate, acetonitrile, dichloromethane, dichloroethane, or a mixed solvent thereof and the like can be used, and THF or dichloromethane is particularly preferable.
  • the kakeromycin derivatives represented by the formulas (1) and (1-1) (excluding kakeromycin) obtained by the production method of the present invention, as well as synthetic intermediates thereof represented by the formulas (2), (3), (4), (5) and (6) are novel compounds.
  • the kakeromycin and a derivative thereof (bicyclic oxaziridine and a derivative thereof) and a synthetic intermediate thereof obtained by the production method of the present invention may be salts.
  • examples of such salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • a pharmaceutically acceptable salt is preferable.
  • the kakeromycin and a derivative thereof (bicyclic oxaziridine and a derivative thereof) obtained by the production method of the present invention have a strong antifungal activity against a broad range of fungi, and are expected to be new antifungal agents.
  • the kakeromycin and a derivative thereof show cytotoxicity against cancer cells. Therefore, a compound containing the kakeromycin or a derivative thereof as an active ingredient can be used as a medicament, a pesticide and the like.
  • fungi examples include, but are not limited to, fungi such as the genus Candida (e.g., Candida albicans , Candida parapsilosis , Candida tropicalis , Candida krusei , Candida glabrata , Candida quilliermondii , Candida lusitaniae etc.), the genus Aspergillus (e.g., Aspergillus fumigatus , Aspergillus flavus , Aspergillus niger , Aspergillus terreus etc.), the genus Trichophyton (e.g., Trichophyton rubrum , Trichophyton mentagrophytes , Trichophyton tonsurans , Microsporum canis , Microsporum gypseum , Trichophyton verrucosum etc.) and the like.
  • Mycosis is not particularly limited, and deep skin mycosis, deep mycosis, mycetoma, and
  • the target crop is not particularly limited and, for example, plants such as grain (e.g., rice, barley, wheat, rye, oats, corn, kaoliang etc.), beans (soybean, adzuki bean, broad bean, pea, peanut etc.), fruit-tree, fruits (apple, citrus, pear, grapes, peach, ume (Japanese plum), cherry, walnut, almond, banana, strawberry etc.), vegetables (cabbage, tomato, spinach, broccoli, lettuce, onion, green onion, bell pepper etc.), root vegetables (carrot, potato, sweet potato, radish, lotus root, turnip etc.), crops for processing (cotton, hemp, kozo (paper mulberry), mitsumata plant, rape seed, beet, hop, sugarcane, sugar beet, olive, rubber, coffee, tobacco, tea etc.), gourds (pumpkin, cucumber, watermelon, melon etc.),
  • the antifungal agent can be used for controlling the diseases related to the aforementioned fungi in the crops, by treating the target crop and/or seed of the target crop with an effective amount thereof.
  • the pesticide can be used at the following form, and generally used together with an adjuvant conventionally used in the pharmaceutical fields.
  • the kakeromycin and a derivative thereof obtained by the production method of the present invention are formulated by a known method into, for example, emulsion stock solution, sprayable paste, sprayable or dilutable solution, dilutable emulsion, wettable agent, water soluble powder, powder, granule, flowable pesticide, dry flowable pesticide, smoking agent, fumigant and, for example, capsule made of a polymer substance.
  • plant-derived powder such as soy flour, wheat flour and the like, mineral fine powder such as diatomaceous earth, apatite, plaster, talc, bentonite, clay and the like, and organic and inorganic compounds such as sodium benzoate, urea, salt cake and the like can be used.
  • liquid dosage form When a liquid dosage form is desired, vegetable oil, mineral oil, kerosene, aromatic hydrocarbons such as xylene and toluene, amides such as formamide, and dimethylformamide, sulfoxides such as dimethyl sulfoxide, ketones such as methyl isobutyl ketone and acetone, trichloroethylene, water and the like are used as solvents.
  • a surfactant can also be added where necessary.
  • the thus-obtained wettable agent, emulsion, aqueous solution, flowable pesticide, and dry flowable pesticide are diluted with water to a given concentration and used as a suspension or emulsion, and powder and granule are used by directly spraying on the soil or plant.
  • the content and dose of the active ingredient in a pesticide containing the kakeromycin or a derivative thereof obtained by the production method of the present invention can be changed in a wide range depending on the dosage form, the kind of fungi to be the application target, target crop and the like.
  • the antifungal agent when used as a medicament, it can be administered to a treatment target, for example, a mammal (e.g., human, mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey etc.) by an oral or parenteral administration route (e.g., intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration).
  • a mammal e.g., human, mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey etc.
  • an oral or parenteral administration route e.g., intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration.
  • the antifungal agent When the antifungal agent is transdermally administered, it can contain, besides the above-mentioned active ingredient, oily base, emulsifier and emulsion stabilizer, solubilizing agents, powder component, polymer component, adhesiveness improver, film-forming agent, pH adjuster, antioxidant, antiseptic agent, preservative, shape retention agent, moisturizer, skin protector, algefacient, flavor, colorant, chelating agent, lubricant, blood circulation promoter, astringent, tissue repair promoter, adiaphoretic, plant extraction component, animal extraction component, antiinflammatory agent, antipruritic agent and the like as necessary.
  • these additives those generally used for preparations can be used.
  • the antifungal agent can be used by formulating the above-mentioned components other than the active ingredient and the like into external drugs such as cream, liquid, lotion, emulsion, tincture, ointment, aqueous gel, oily gel, aerosol, powder, shampoo, soap, enamel agent for application to nail and the like, by a method conventionally used in the field of pharmaceutical preparations.
  • external drugs such as cream, liquid, lotion, emulsion, tincture, ointment, aqueous gel, oily gel, aerosol, powder, shampoo, soap, enamel agent for application to nail and the like, by a method conventionally used in the field of pharmaceutical preparations.
  • the antifungal agent When the antifungal agent is orally administered, it can be prepared into a dosage form suitable for oral administration such as capsule, tablet, granule, powder, pill, fine granules, troche and the like. These preparations can be produced using additives generally used for oral preparations, such as excipient, filler, binder, moistening agent, disintegrant, surfactant, lubricant, dispersing agent, buffering agent, preservative, solubilizing agent, antiseptic agent, flavoring agent, soothing agent, stabilizer and the like by a conventional method.
  • additives generally used for oral preparations such as excipient, filler, binder, moistening agent, disintegrant, surfactant, lubricant, dispersing agent, buffering agent, preservative, solubilizing agent, antiseptic agent, flavoring agent, soothing agent, stabilizer and the like by a conventional method.
  • Examples of the cells to be the target of the anticancer agent include, but are not limited to, cancer cells such as HepG2 cell (liver cancer cell), PANC1 cell (pancreas cancer cell) and the like.
  • the cancer is not particularly limited, and brain tumor, skin cancer, leukemia, esophagus cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, rectal cancer, osteosarcoma and the like can be mentioned.
  • Oxime 8a-01 52 mg, 0.30 mmol
  • N-Boc-aminobutene 7A-01 62 mg, 0.36 mmol
  • THF 5 mL
  • aqueous sodium hypochlorite solution 5%, 2 mL
  • Sodium sulfate 5 g was added to remove water in the reaction system, and the mixture was filtered through cotton. The obtained filtrate was concentrated by a rotary evaporator.
  • N-Boc aminohydroxyketone 5Aa-001 (50 mg, 0.14 mmol) was dissolved in dichloroethane (3 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated by a rotary evaporator to give a mixture (31 mg, 0.13 mol) of aminohydroxyketone 4Aa-001 and cyclic hemiaminal 3Aa-001 as yellow liquid (yield 87%).
  • Cyclic imine 2Aa-001 (9 mg, 0.039 mmol) was dissolved in THF (3 mL), m-chloroperbenzoic acid (11 mg) was added, and the mixture was stirred at room temperature for 3 hr and concentrated by a rotary evaporator.
  • the obtained crude product was purified by silica gel column chromatography (solvent: hexane and ethyl acetate) to give bicyclic oxaziridine 1Aa-001 (3 mg, 0.012 mmol) as yellow liquid (yield 31%).
  • N-Boc aminohydroxyketone 5A-01 was obtained as colorless liquid (yield 69%).
  • 1 H NMR (300 MHz, CDCl 3 ): ⁇ 0.83 (t, 3H, J 7.5 Hz), 1.16-1.76 (m, 10H), 1.40 (s, 9H), 2.32-2.60 (m, 6H), 3.16-3.44 (m, 2H), 4.00-4.26 (m, 1H), 4.96-5.04 (br, 1H).
  • N-Boc aminohydroxyketone 5A-02 was obtained as colorless liquid (yield 69%).
  • N-Boc aminohydroxyketone 5A-03 was obtained as colorless liquid (yield 67%).
  • N-Boc aminohydroxyketone 5A-04 was obtained as colorless liquid (yield 62%).
  • oxime 8a-02 was obtained as a colorless solid (yield 90%).
  • N-Boc aminohydroxyketone 5Aa-002 was obtained as colorless liquid (yield 62%).
  • 1 H NMR (300 MHz, CDCl 3 ): ⁇ 1.43 (s, 9H), 2.56-2.82 (m, 7H), 3.02-3.44 (m, 3H), 3.82 (s, 2H), 4.02-4.16 (m, 1H), 4.92-5.02 (br, 1H), 6.81 (t, 1H, J 6.6 Hz), 7.10-7.38 (m, 10H).
  • oxime 8a-03 was obtained as a colorless solid (yield 85%).
  • N-Boc aminohydroxyketone 5Aa-003 was obtained as colorless liquid (yield 66%).
  • 1 H NMR (300 MHz, CDCl 3 ): ⁇ 1.42 (s, 9H), 1.50-1.70 (m, 2H), 1.76 (s, 3H), 1.84 (d, 3H, J 6.6 Hz), 2.72-2.82 (m, 2H), 3.10-3.42 (m, 2H), 4.12-4.20 (m, 1H), 4.96-5.10 (br, 1H), 6.70-6.82 (m, 1H) .
  • oxime 8a-04 was obtained as a colorless solid (yield 87%).
  • N-Boc aminohydroxyketone 5Aa-004 was obtained as colorless liquid (yield 65%).
  • kakeromycin and a derivative thereof showing an antifungal activity and cytotoxicity and expected as a new antifungal agent or anticancer agent, by chemical synthesis is provided.

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US20220024883A1 (en) 2022-01-27
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